title: CYP2A5 induction and hepatocellular stress: an adaptive response to perturbations of heme homeostasis.
abstract: Unlike most cytochrome P450 (CYP) enzymes, murine hepatic CYP2A5 is induced during pathological conditions that result in liver injury including hepatotoxicity mediated by xenobiotics, hepatitis caused by various microbial agents and liver neoplasia. Since CYP2A5 metabolizes various important xenobiotics including nicotine and pro-carcinogens such as nitrosamines and aflatoxin B(1), altered gene expression could affect tobacco addiction, hepatotoxicity and hepatocarcinogenesis. This article synthesizes the current knowledge concerning hepatic expression of Cyp2a5 including the transcriptional and post-transcriptional regulatory mechanisms, pathophysiological conditions associated with enzyme induction such as oxidative and endoplasmic reticulum stress and altered lipid and energy homeostasis as well as the known exogenous and putative endogenous substrates. Knowledge of the stimuli responsible for the unique overexpression of CYP2A5 during liver injury may provide clues to a functional role for this enzyme and the impact of variable CYP2A5 expression on xenobiotic metabolism and toxicity, disease development and the adaptive response to hepatocellular stress.
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ontario, Canada. gkirby@uoguelph.ca
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Kirby
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Nichols
authors.forename: Monica
authors.initials: M
authors.lastname: Antenos
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D065637:Cytochrome P-450 CYP2A6; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D011166:Porphyrins / Q000378:metabolism / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011166:Porphyrins; D011720:Pyrazoles; D014157:Transcription Factors; D015262:Xenobiotics; C031280:pyrazole; D006418:Heme; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6